Neurobeachin and the Kinesin KIF21B Are Critical for Endocytic Recycling of NMDA Receptors and Regulate Social Behavior

Cell Rep. 2018 May 29;23(9):2705-2717. doi: 10.1016/j.celrep.2018.04.112.

Abstract

Autism spectrum disorders (ASDs) are associated with mutations affecting synaptic components, including GluN2B-NMDA receptors (NMDARs) and neurobeachin (NBEA). NBEA participates in biosynthetic pathways to regulate synapse receptor targeting, synaptic function, cognition, and social behavior. However, the role of NBEA-mediated transport in specific trafficking routes is unclear. Here, we highlight an additional function for NBEA in the local delivery and surface re-insertion of synaptic receptors in mouse neurons. NBEA dynamically interacts with Rab4-positive recycling endosomes, transiently enters spines in an activity-dependent manner, and regulates GluN2B-NMDAR recycling. Furthermore, we show that the microtubule growth inhibitor kinesin KIF21B constrains NBEA dynamics and is present in the NBEA-recycling endosome-NMDAR complex. Notably, Kif21b knockout decreases NMDAR surface expression and alters social behavior in mice, consistent with reported social deficits in Nbea mutants. The influence of NBEA-KIF21B interactions on GluN2B-NMDAR local recycling may be relevant to mechanisms underlying ASD etiology.

Keywords: KIF21B; NMDA receptor; Rab GTPase; autism spectrum disorder; dynein; endosomal recycling; neurobeachin; retromer; social behavior; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal*
  • COS Cells
  • Carrier Proteins / metabolism*
  • Chlorocebus aethiops
  • Cognition
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Dyneins / metabolism
  • Endocytosis* / drug effects
  • Endosomes / metabolism
  • Glutamic Acid / pharmacology
  • Golgi Apparatus / drug effects
  • Golgi Apparatus / metabolism
  • Kinesin / metabolism*
  • Membrane Proteins
  • Mice, Knockout
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Nocodazole / pharmacology
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Social Behavior*
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / metabolism
  • rab4 GTP-Binding Proteins / metabolism

Substances

  • Carrier Proteins
  • Kif21b protein, mouse
  • Membrane Proteins
  • NR2B NMDA receptor
  • Nbea protein, mouse
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Dyneins
  • Kinesin
  • rab4 GTP-Binding Proteins
  • Nocodazole